Dry eye disease (DED) is an important and prevalent public health concern for older Americans that is associated with nearly $4 billion in direct and $55 billion in indirect costs annually. VITAL-DED proposes to study the efficacy of marine omega-3 fatty acid (FA) supplementation for the prevention of DED, as well as the long-term amelioration of its associated chronic ocular surface pain and quality of life impacts, which include problems reading and driving. The study will leverage invaluable resources and data from the VITamin D and OmegA-3 TriaL (VITAL, 1U01CA138962), a randomized, double-blind, placebo-controlled, 2x2 factorial trial to test marine omega-3 FA (465 mg/d eicosapentaenoic acid + 375 mg/d docosahexaenoic acid) and vitamin D3 (cholecalciferol, 2000 IU/d) supplements in the primary prevention of cancer and cardiovascular disease among 20,000 men and women aged >50 y & >55 y, respectively. Beginning in July 2011 and continuing throughout 2012, willing and eligible respondents to an invitational mailing will be enrolled in a month run-in, and subsequently those who remain willing, eligible, and compliant during the run-in will be randomly assigned to omega-3 FA or a matching placebo and vitamin D3 or a matching placebo. At 1-year intervals, participants will receive a new supply of pills and a follow up questionnaire on compliance, side effects, and incidence of health endpoints. We propose to ascertain prevalent (pre-randomization) and incident (post-randomization) DED endpoints in the VITAL trail. The primary Specific Aims of VITAL-DED are to test whether omega-3 FA supplementation: 1) reduces the incidence of DED, 2) improves the natural history of DED by relieving symptoms and other impacts on quality of life. Secondary Aims will estimate the incidence of DED in the US, prospectively examine the natural history of DED, explore factors that could modify or influence the impact of omega-3 FA supplementation, evaluate the inter-relationship of DED and depression, and test for possible independent or joint effects of vitamin D3 supplementation in the incidence and natural history of DED. This research is responsive to a program priority of the National Eye Institute's Strategic Plan to improve our understanding of and develop preventive strategies for inflammatory corneal and ocular surface diseases; and also addresses several issues identified in the recent 2010 NEI Workshop on Ocular Pain and Sensitivity. The hypotheses are supported by a compelling biological rationale and strong preliminary data from our prior epidemiological studies, as well as from laboratory investigations and small randomized trials, which suggest that omega-3 FA supplementation, could prevent DED and improve its natural history. We believe the timely start of VITAL-DED offers a unique but time-sensitive opportunity to obtain a reliable, efficient, and informative evaluation of the efficacy of the most promising preventive agent for DED. Given our success with prior large simple trials, our experience with DED, and our proposed methodology, we think VITAL-DED will provide definitive results to guide public health and clinical recommendations for DED prevention and management.